EP0819127A1

EP0819127A1 - IMIDAZO [1,2-a]PYRIDINE DERIVATIVES

Info

Publication number: EP0819127A1
Application number: EP96909164A
Authority: EP
Inventors: Paul J. Glaxo Research and Dev. Ltd. BESWICK; Ian B. Glaxo Research and Dev. Ltd. CAMPBELL; Alan Glaxo Research and Development Ltd. NAYLOR
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1995-04-04
Filing date: 1996-04-02
Publication date: 1998-01-21
Also published as: IS4570A; WO1996031509A1; HUP9801602A3; BG101934A; NO974595D0; JPH11501049A; EA199700209A1; NO974595L; CN1186492A; CZ313397A3; SK133297A3; NZ304886A; MX9707379A; PL322623A1; CA2216809A1; AU5276696A; HUP9801602A2; KR19980703559A; TR199701105T1

Abstract

The invention provides the compounds of formula (I) and pharmaceutically acceptable derivatives thereof in which: R0 represents halogen; R?1 and R2¿ are independently selected from H, halogen, C¿1-4?alkyl, C1-4alkyl substituted by one or more fluorine atoms, C1-4alkoxy, C1-4hydroxyalkyl, SC1-4alkyl, C(O)H or C(O)C1-4alkyl; and R?3¿ represents C¿1-4?alkyl. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever, inflammation of a variety of conditions and diseases.

Description

IMIDAZO [l,2a ] PYRIDINE DERIVATIVES

This invention relates to imidazo[1 ,2-a]pyridine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

The enzyme cyclooxygenase (COX) has recently been discovered to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. Prostaglandins generated by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is responsible for the important physiological functions such as maintenance of gastrointestinal integrity and renal blood flow. In contrast the inducible form, COX-2, is believed to be responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inflammatory agents, hormones, growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1. We have now found a novel group of compounds which are both potent and selective inhibitors of COX-2.

The invention thus provides the compounds of formula (I)

and pharmaceutically acceptable derivatives thereof in which:

R° represents halogen;

R¹ and R² are independently selected from H, halogen, d^alkyl, C_.^alkyl substituted by one or more fluorine atoms,

SCι_,alkyl, C(O)H or C(0)C._.alkyl; and R³ represents Chalky!. By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester, of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.

The term halogen is used to represent fluorine, chlorine, bromine or iodine.

The term 'alkyl' as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.

The substituents R¹ and R² may be at the 5-, 6-, 7- or 8- positions of the pyridine ring of formula (I), as defined hereinbelow:

Preferably, R¹ is at the 8- position; and R² is at the 7- position or, when R¹ is other than H, the 5-, 6- or 7-position. More preferably, R¹ is at the 8- position; and R² is at the 7- position or, when R¹ is Cι_ιalkyl (e.g. methyl), the 5- or 7- position.

Preferably, R° represents fluorine.

Preferably, R¹ represents H, chlorine, bromine, d^alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH₂F or CF₃), C.^hydroxyalkyl (e.g. CH₂OH or CH(OH)CH₃), SCι_.alkyl (e.g. SCH₃), C(0)H or C(0)C. ,alkyl (e.g. C(0)CH ). More preferably, R¹ represents H, chlorine, bromine, methyl, CH₂F, CF₃, SCH₃, C(0)H or C(0)CH₃. Most preferably R¹ represents C(0)CH₃.

Preferably, R² represents H, chlorine, bromine, or C._.alkyl (e.g. methyl). More preferably, R² represents H, bromine or methyl.

Preferably, R³ represents methyl.

Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R° represents fluorine; R¹ represents H, chlorine, bromine, (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH₂F or CF₃), C._,hydroxyalkyl (e.g. CH₂OH or CH(OH)CH₃), SC....alkyl (e.g.

SCH₃), C(0)H or C(0)C. ,alkyl (e.g. C(0)CH₃); R² represents H, chlorine, bromine, or C_._»alkyl (e.g. methyl); and R³ represents methyl.

Within group A there is provided the sub-group of compounds wherein: R° represents fluorine; R¹ represents H, chlorine, bromine, methyl, CH₂F, CF₃, SCH₃, C(O)H or C(0)CH₃; R² represents H, bromine or methyl; and R³ represents methyl.

Within the invention there is provided another group of compounds of formula (I) (group B) wherein R° represents fluorine; R¹ is at the 8- position and represents H, chlorine, bromine, C.^alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH₂F or CF₃), C.^hydroxyalkyl (e.g. CH₂OH or

CH(OH)CH₃), SC._.alkyl (e.g. SCH₃), C(0)H or C(0)C._,alkyl (e.g. C(0)CH₃); R² is at the 7- position or, when R¹ is other than H, the 5-, 6- or 7- position, and represents H, chlorine, bromine, or Cι_,alkyl (e.g. methyl); and R³ represents methyl.

Within group B there is provided the sub-group of compounds wherein: R° represents fluorine; R¹ is at the 8- position and represents H, chlorine, bromine, methyl, CH₂F, CF₃, SCH₃, C(0)H or C(0)CH₃; R² is at the 7- position or, when R¹ is methyl, the 5- or 7- position, and represents H, bromine or methyl; and R³ represents methyl.

Within the invention there is provided a further group of compounds of formula

(I) (group C) wherein R° represents fluorine; R¹ is at the 8- position and represents H, chlorine, bromine, C^alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH₂F or CF₃), C^hydroxyalkyl (e.g. CH₂OH or CH(OH)CH₃), SC^alkyl (e.g. SCH₃), C(0)H or C(0)C^alkyl (e.g. C(0)CH₃); R² represents H; and R³ represents methyl.

Within group C there is provided the sub-group of compounds wherein: R° represents fluorine; R¹ is at the 8- position and represents H, chlorine, bromine, methyl, CH₂F, CF₃, CH(OH)CH₃, SCH₃, C(0)H or C(0)CH₃; R² represents H; and R³ represents methyl.

Within the above groups (and preferred groups) of compounds, especially preferred groups of compounds are those wherein R¹ represents C(0)CH₃.

It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).

Preferred compounds of the invention are:

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine;

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methyl-imidazo[1,2- a]pyridine;

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-^β-trifluoromethyl-imidazo[1,2- a]pyridine;

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl)-7-methyl-imidazo[1 ,2-a]pyridine;

8-chloro-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2- a]pyridine;

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methanesulfanyl- imidazo[1 ,2-a]pyridine;

8-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2- a]pyridine;

8-fluoromethyl-3-(4-fluoro-phenyl)-2-(4-methanesulphonyl-phenyl)-imidazo[1 ,2- a]pyridine; 3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-7,8-dimethyl-imidazo[1,2- ajpyridine;

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine-8- carbaldehyde; 5-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methyl- imidazo[1 ,2-a]pyridine;

6-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methyl- imidazo[1 ,2-a]pyridine; [3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]- methanol;

(±) 1 -[3-(4-fluoro-phenyl)-2-(4-methanesulphonyl-phenyl)-imidazo[1 ,2-a]pyridin- 8-yl]-ethan-1-ol; and pharmaceutically acceptable derivatives thereof.

A particularly preferred compound of the invention is:

8-acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2- ajpyridine; and pharmaceutically acceptable derivatives thereof.

Compounds of the invention are potent and selective inhibitors of COX-2. This activity is illustrated by their ability to selectively inhibit COX-2 over COX-1.

In view of their selective COX-2 inhibitory activity, the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment of the pain, fever and inflammation of a variety of conditions and diseases. Such conditions and diseases are well known in the art and include rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.

The compounds of the invention may also be useful for the treatment of other conditions mediated by selective inhibition of COX-2.

For example, the compounds of the invention may inhibit cellular and neoplastic transformation and metastatic tumour growth and hence be useful in the treatment of certain cancerous diseases, such as colonic cancer.

Compounds of the invention may also prevent neuronal injury by inhibiting the generation of neuronal free radicals (and hence oxidative stress) and therefore may be of use in the treatment of stroke; epilepsy; and epileptic seizures (including grand mal, petit mal, myoclonic epilepsy and partial seizures).

Compounds of the invention also inhibit prostanoid-induced smooth muscle contraction and hence may be of use in the treatment of dysmenorrhoea and premature labour.

Compounds of the invention inhibit inflammatory processes and therefore may be of use in the treatment of asthma, allergic rhinitis and respiratory distress syndrome; gastrointestinal conditions such as inflammatory bowel disease, Chron's disease, gastritis, irritable bowel syndrome and ulcerative colitis; and the inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, conjunctivitis and myocardial ischemia.

Compounds of the invention may also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye tissue.

Compounds of the invention may also be useful for the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea,

Parkinson's disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated

Memory Impairment.

According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.

According to another aspect of the invention, we provide a compound of formula

(I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by selective inhibition of COX-2. According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from a condition which is mediated by selective inhibition of COX-2 which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative.

According to another aspect of the invention, we provide the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment of inflammatory disorders.

According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.

It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more other therapeutic agents. Examples of suitable agents for adjunctive therapy include pain relievers such as a glycine antagonist, a sodium channel inhibitor (e.g. lamotrigine), a substance P antagonist (e.g. an NKi antagonist), acetaminophen or phenacetin; a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor (e.g. an iNOS or an nNOS inhibitor); an inhibitor of the release, or action, of tumour necrosis factor α; an antibody therapy (e.g. a monoclonal antibody therapy); a stimulant, including caffeine; an H₂-antagonist, such as ranitidine; an antacid, such as aluminium or magnesium hydroxide; an antiflatulent, such as simethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antitussive, such as codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan; a diuretic; or a sedating or non-sedating antihistamine. It is to be understood that the present invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents. The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.

Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.

The compounds of formula (I) and their pharmaceutically acceptable derivatives may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration. The pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (I) and their pharmaceutically acceptable derivatives.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets (including sub-lingual tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.

For transdermal administration, the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.

For parenteral administration, the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously). The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.

Alternatively for parenteral administration the active ingredient may be in powder form for reconstitution with a suitable vehicle.

The compounds of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

As stated above, the compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

A proposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 500 mg/kg, such as 0.05mg/kg to 100mg/kg, e.g. 0.1mg/kg to 50mg/kg, which may be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0.25mg/kg to 10mg/kg may be suitable for systemic administration.

Compounds of formula (I) and pharmaceutically acceptable derivatives thereof may be prepared by any method known in the art for the preparation of compounds of analogous structure. Suitable methods for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof are described below. In the formulae that follow R°to R³are as defined in formula (I) above unless otherwise stated and Lg represents a leaving group, such as a sulphonate (e.g. methanesulphonate) or a halogen (e.g. bromine).

Thus according to a first process (A), compounds of formula (I) may be prepared by reacting a compound of formula (II)

or a protected derivative thereof with a compound of formula (III)

or a protected derivative thereof. The reaction is conveniently carried out in a solvent, such as a polar solvent (e.g. acetonitrile or isopropanol); at elevated temperature, e.g. reflux; and optionally in the presence of a base, such as an alkali metal bicarbonate or carbonate (e.g. potassium carbonate).

Suitable leaving atoms or groups in respect of Lg in formula (II) are described in many standard texts on organic chemistry, for example in table 10.10 on page 357 of 'Advanced Organic Chemistry' by Jerry March, fourth edition (Wiley, 1992). It will be appreciated by a person skilled in the art that the choice of a particular leaving group in the above reaction may depend upon the meanings of R° to R³ (and hence the compound of formula (I) desired) and the reaction conditions employed. According to a another process (B), compounds of formula (I) may be prepared by reacting a compound of formula (I )

or a protected derivative thereof with an oxidising agent. Convenientl the oxidation is effected using a monopersulfate compound, such as potassium peroxymonosulfate (known as Oxone™) and the reaction is carried out in a solvent, such as an aqueous alcohol, (e.g. aqueous methanol), and at between -78°C and ambient temperature.

According to another process (C) compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors.

Thus, for example, compounds of formula (I) wherein R¹ or R² represent chlorine, bromine or iodine may be prepared from the corresponding compound of formula (I) wherein R¹ or R² represent H, by treatment with an appropriate halogenating agent (i.e. chloro-, bromo- or iodinating agent). Suitable agents include the corresponding N-halosuccinimdes. Conveniently the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. chloroform), and at ambient temperature.

Compounds of formula (I) wherein R¹ or R² represent substituted by one or more fluorine atoms may be prepared from the compound of formula (I) wherein R¹ or R² represents the corresponding by treatment with a suitable source of fluorine. Suitable sources of fluorine include, for example, diethylaminosulphur trifluoride. Conveniently the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. dichloromethane), and at reduced temperature, such as -78°C.

Compounds of formula (I) wherein R¹ or R² represent C(0)H may be prepared from the corresponding compound of formula (I) wherein R¹ or R² represent CH₂OH by oxidation. Suitable oxidising agents include, for example, manganese (IV) oxide. Conveniently the oxidation is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. chloroform), and at elevated temperature (e.g. reflux).

Compounds of formula (I) wherein R¹ or R² represent C_.^hydroxyalkyl, and wherein the hydroxy group is attached to the carbon linked to the pyridine ring, may be prepared by reduction of the compound of formula (I) wherein R¹ or R² represent the corresponding aldehyde or ketone. Suitable reducing agents include hydride reducing agents, such as diisobutylaluminium hydride. Conveniently the reduction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. dichloromethane), and at reduced temperature, such as -78°C.

As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the above described processes to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.

Another process (D) for preparing compounds of formula (I) thus comprises deprotecting protected derivatives of compounds of formula (I).

The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W. Green, second edition, (John Wiley and Sons, 1991), which also describes methods for the removal of such groups.

Compounds of formula (II) may be prepared from compounds of formula (V)

by conventional means.

Thus, compounds of formula (II) wherein Lg represents a halogen may be prepared from compounds of formula (V) by treatment with a halogenating agent, at reduced temperature and in a solvent, such as a chlorinated hydrocarbon. For example, where Lg represents bromine, the reaction is conveniently effected with a brominating agent, such as bromine in the presence of a strong acid (e.g. hydrobromic acid in acetic acid).

Compounds of formula (II) wherein Lg represents a sulphonate may be prepared from compounds of formula (V) firstly by oxidation to the corresponding α-hydroxy . ketone, followed by treatment with a sulphonating agent. Suitable oxidising agents include, for example, Pb(OAc)₄, dimethyldioxirane and those described in F A Davis, J. Org. Chem., 1984, 49(17). 3284. Suitable sulphonating agents include sulphonylhalides, such as sulphonylchlorides (e.g. methanesulphonylchloride). The sulphonylation is conveniently effected in the presence of a base, such as an amine (e.g. triethylamine); and in a solvent, such as a halogenated hydrocarbon.

Compounds of formula (V) may be prepared from compounds of formula (VI)

by treatment with an alkali sulphinate, such as a sodium sulphinate. Conveniently, the reaction is carried out in a polar solvent, such as dimethyl sulphoxide, and at elevated temperature.

Compounds of formula (III) are either known compounds or may be prepared by literature methods such as those described in, for example, J A Turner, J. Org. Chem., 1983, __ 3401; M Malinowski, Bull. Soc Chim. Belg., 1988, 9∑ 51; W O Siegl, J. Het. Chem., 1981, 18, 1613-18; or F. Trecourt et al, J. Chem. Soc, Perkin Trans.1 1990, 9, 2409-2415.

Compounds of formula (VI) are either known compounds or may be prepared by literature methods such as those described in, for example, N Seko et al. Chem. Pharm. Bull., 1991, 3_ (3), 651-7, or / Lalazori et al. J.Med.Chem. 1971, 14, 1138-40.

Compounds of formula (IV) or protected derivatives thereof may be prepared using conventional chemistry, for example chemistry analogous to that herein described for the preparation of compounds of formula (I).

Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention. Compounds of formula (II) and (IV) are key intermediates and represent particular aspects of the present invention.

Conveniently, compounds of the invention are isolated following work-up in the form of the free base. Pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared using conventional means.

Solvates (e.g. hydrates) of a compound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.

The following Examples illustrate the invention but do not limit the invention in any way. All temperatures are in °C. Flash chromatography was carried out using Merck 9385 silica. Thin layer chromatography (Tic) was carried out on silica plates. NMR was carried out on a Brucker 300Mhz spectrometer, using CDCI₃ as solvent. Chemical shifts are given in δ ppm with respect to tetramethylsilane as internal chemical shift reference. The following abbreviations are used: Et = ethyl, s = singlet, d = doublet, t = triplet and m = multiplet.

Intermediate 1

2-(4-Fluoro-phenylV1-(4-methanesulfonyl-phenyl_-ethanone

A mixture of the 2-(4-fluoro-phenyl)-1-(4-fluoro-phenyl)-ethanone¹ (3g) and sodium methane sulphinate (1.58g) in dry dimethyl sulphoxide (10ml) was heated to 105-110° under nitrogen for 18h. The cooled reaction mixture was poured into water (500ml) and the mixture extracted with ethyl acetate. The combined organic extracts were adsorbed onto silica and purified by flash chromatography eluting with ethyl acetate:hexane (1:1) to give the title compound as a white solid (2.1 g). m.p. 115-116° ¹ Ref: I Lalazori e _, J.Med.Chem. 1971 , 14. 1138-40. Intermediate 2

2-Bromo-2-(4-fluoroH3henvπ-1-(4-methanesutfonyl-phenvπ-ethanone A solution of the 2-(4-fluoro-phβnyl)-1-(4-methanesulfonyl-phenyl)-ethanone (1.6g) in dichloromethane (30ml) and glacial acetic acid (15ml) was cooled to 0° and treated with 48% hydrobromic acid (3 drops). A solution of bromine

(875mg) in acetic acid (2ml) was added and stirring continued for 4 hours. The mixture was diluted with dichloromethane (35ml) and the solution was washed with water, dried, and concentrated to give the title compound as a yellow solid (2-Og). m.p. 124-126°

Intermediate 3

3-Trifluoromethyl-pyridin-2-ylamine

A mixture of 2-chloro-3-trifluoromethyl-pyridine (5g), copper(1 ) iodide (5g) and liquid ammonia (50ml) was heated in an autoclave at 80° (internal temperature) for 28 hours. The cooled reaction mixture was slurried with methanol/chloroform (1/1-250 ml) and filtered. The filtrate was absorbed onto silica and purified by flash chromatography eluting with ethyl acetate/hexane

(1/1 ), to yield the title compound as a white solid (1.4g). m.p. 71-72° MH^* = 163

Tic SiO₂, Rf 0.50 (ethyl acetate/hexane (1/1)) detection UV/KMn0₄

Intermediate 4

2-(4-Fluoro-phenyl)-1-(4-methanesulfanyl-phenyl)-ethanone A mixture of 2-(4-fluoro-phenyl)-1-(4-fluoro-phenyl)-ethanone (10.0g) sodium methanethiolate (3.0g) and dimethyl sulphoxide (10ml) was heated at -100° for

8h under nitrogen. The cooled mixture was added to water (250ml), stirred for 10 min and filtered. The resulting solid was crystallised from isopropanol (100ml) twice to give the title compound as a white solid (5.0g). m.p. 143-144°

Intermediate 5

2-Bromo-2-(4-fluoro-phenvh-1-(4-methanesulfanyl-phenyl.-ethanone A solution of 2-(4-fluoro-phenyl)-1-(4-methanesulfanyl-phenyl)-ethanone (4.8g) in dichloromethane (75ml) and acetic acid (30ml) at 0° containing 48% HBr (15 drops) was treated dropwise with bromine (2.6g), in acetic acid (6ml). The solution was stirred at 0° for 10 min and at room temperature for 3h, diluted with dichloromethane (100ml) and washed with water (2 x 100ml). The dried (MgSO ) organic phase was evaporated and the residue was triturated with diethyl ether (30ml) to give the title compound as a white solid (4.5g). m.p. 117-119°.

Tic Si0₂ (Et₂0:hexane 1:1) Rf 0.6 det u.v. KMn0₄, isopropanol.

Intermediate 6

3-(4-Fluoro-phenyl_-2-_4-methanesulfanyl-phenyl_-imidazoH .2-alPyridine

A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfanyl-phenyl)- ethanone (4.0g) and 2-aminopyridine (1.2g) in acetonitrile (25ml) was retluxed under nitrogen for 2h and left at room temperature for 16h. The solution was evaporated and the residue purified by flash column chromatography eluting with diethyl ether (applied in CH₂CI₂) to give the title compound as a white solid d -6g). m.p. 115-118°

Tic Si0 (Et₂0) Rf 0.5 det u.v., isopropanol.

Intermediate 7

8-Chloro-3-(4-fluoro-phenyl.-2-f4-methanesulfanyl-phenyl)-imidazoπ.2- alpyridine rvButyllithium in hexane (1.6m; 0.35ml) was added dropwise to a solution of 3-

(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1 ,2-a]pyridine (167mg) in tetrahydrofuran (2ml) at -78° under nitrogen. The solution was stirred at -78° for 1h and was treated with hexachloroethane (142mg) in tetrahydrofuran

(0.25ml). The solution was allowed to warm to room temperature during 30 min and water (2ml) was added. The mixture was extracted with ethyl acetate (2 x

5ml) and the dried (MgSO ) extract was evaporated to give the title compound as a cream solid (180mg). m.p. 148-149°

MH⁺ = 369

Intermediate 8

3-Methylsulfanyl-pyridin-2-ylamine

A solution of 2,2-dimethyl-N-pyridin-2-yl-propionamide² (890mg) in dry tetrahydrofuran (30ml) was cooled to -78° and treated with a solution of n-butyl lithium (6.25 ml,1.6M). This solution was stirred at 0° for 4 hours and a solution of dimethyldisulphide (235mg) in tetrahydrofuran (5ml) was added and stirring continued at ambient temperature for 30 minutes. 2N Hydrochloric acid (1ml) was added and the solution concentrated in vacuo. A mixture of the residue and 2N hydrochloric acid (15ml) was heated at reflux for 4 hours. The cooled reaction mixture was made basic by addition of solid potassium carbonate. The basic mixture was extracted with ethyl acetate (15ml),the organic extract was dried (Na₂S0₄) and absorbed onto silica. The title compound was obtained by flash chromatogrphy eluting with ethyl acetate/cyclohexane (1/1 ) as a colourless oil (490mg). MH⁺ = 141

Tic, Si0₂, Rf 0.48, (ethyl acetate/cyclohexane(1/1)) detection u.v., KMn0₄ ² Ref: J A Turner J. Org. Chem. 1983.48.3401

Intermediate 9 3-(4-Fluoro-phenvπ-2-(4-methanesulfonyl-phenvπ-imidazof1.2-alPyridine-8- carboxylic acid methyl ester

A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)- ethanone (700mg), and 2-amino-nicotinic acid methyl ester (287mg) in dry acetonitrile was heated at reflux overnight. The reaction mixture was concentrated onto silica and the title compound obtained by flash chromatography eluting with ethyl acetate yclohexane 5:1 as a yellow solid

(176mg). MH⁺ = 425 Tic, Si0₂ Rf 0.21 (ethyl acetate:cyclohexane 5:1 ) detection uv

Intermediate 10 8-Acetyl-3-(4-fluoro-phenyl_-2-(4-methanesulfanyl-phenyl_-imidazof1 ,2- a.pyridine jvButyllithium in hexane (1.6m; 0.5ml) was added dropwise to a solution of 3-(4- fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1 ,2-a]pyridine (250mg) in tetrahydrofuran (3ml) at -78° under nitrogen. The solution was stirred at -78° for 1h and was treated with N-methyl.N-methoxyacetamide (90mg) in tetrahydrofuran (0.25ml). The solution was allowed to warm to room temperature during 60min and water (10ml) was added. The mixture was extracted with ethyl acetate (2 x 5ml) and the dried (MgSO₄) extract was evaporated. The residue was purified on a column of silica, eluting with hexane:diethylether (3:1 ) to give the title compound as a cream solid (130mg). MH⁺ = 377 Tic Si0₂ (Et₂0) Rf 0.9 det u.v.

Example 1

3- 4-Fluoro-phenyl)-2-(4-methanesulfonyl-phenvπ-imidazof1.2-alPyridine A solution of the 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)- ethanone (233mg) and 2-aminopyridine (59mg) in dry acetonitrile was heated at reflux overnight. The reaction mixture was adsorbed onto silica and purified by flash chromatography eluting with ethyl acetate to afford the title compound as a cream solid (100mg). MH⁺ = 367.2 m.p. 198-200°

Example 2 3-(4-Fluoro-phenvπ-2-(4-methanesulfonyl-phenyl.-8-methyl-imidazoπ .2- alpyridine

A solution of the 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)- ethanone (233mg) and 2-amino-3-methylpyridine (68mg) in dry acetonitrile

(10ml) was heated at reflux overnight. The reaction mixture was adsorbed onto silica and purified by flash chromatography eluting with dichloromethane/methanol (19:1 ) to afford the title compound as a pale brown solid (61 mg).

MH⁺ = 381 m.p. 180-182°

Example 3

3-(4-Fluoro-phenyl -2-(4-methanesulfonyl-phenvπ-8-trifluoromethyl-imidazo[1.2- alpyridine

A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)- ethanone (742mg), and 3-trifluoromethyl-pyridin-2-ylamine (324mg,) in dry acetonitrile containing potassium carbonate (276mg) was heated at reflux overnight. The reaction mixture was concentrated onto silica and purified by flash chromatography eluting with ethyl acetate, to give a yellow solid. Further purification by recrystallisation from propan-2-ol yielded the title compound as yellow crystals (210mg). m.p. 260-261°

Analysis: Found: C.57.7; H.3.0; N.6.2; S.7.3 C₂iHι₄F₄N₂O₂S Requires: C.58.1; H.3.25; N.6.45; S,7.4%

MH⁺ = 435 Tic, Si0₂, Rf 0.25, (ethyl acetate) detection u.v.

Example 4

3- -Fluoro-phenyl)-2-(4-methanesulphonyl_-7-methyl-imidazoM .2-atoyridine A solution of the 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)- ethanone (233mg) and 2-amino-4-methylpyridine (68mg) in acetonitrile 10ml) was heated at reflux for 18 hours. The cooled reaction mixture was absorbed onto silica and the title compound obtained by flash chromatography, eluting with ethyl acetate /hexane (1/1), as a buff solid (105mg). m.p.194-196°

MH⁺ = 381

Tic, Si0₂, Rf 0.26, (ethyl acetate/hexane (2/1 )) detection u.v.

Example 5

8-Chloro-3-(4-fluoro-phenyl.-2-(4-methanesulfonyl-phenvπ-imidazoπ .2- alpyridine

A suspension of 8-chloro-3-(4-fluoro-phenyl)-2-(4-methanesuifanyl-phenyl)- imidazo[1 ,2-a]pyridine (150mg) in methanol (8ml) and water (2ml) was treated with Oxone ™ (561 mg) and stirred for 2h at room temperature. The resulting suspension was treated with water (50ml) and extracted with ethyl acetate (2 x 50ml). The dried (MgS0₄) extract was evaporated and the resulting solid was treated with boiling isopropanol (8ml) for (10min) cooled and filtered to give the title compound as a white solid (85mg). m.p. 242-244°

Tic SiO₂ (Et₂O) RF 0.5 det u.v., KMn0₄ MH⁺ = 401 Example 6

3- 4-Fluoro-phenyl_-2- 4-methanesulfonyl-phenvπ-8-methanesulfanyl- imidazof 1.2-alpyridine

A solution of 3-methylsulfanyl-pyridin-2-ylamine (140 mg) and 2-bromo-2-(4- fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (371 mg) in acetonitrile

(15ml) was heated at reflux overnight. The cooled reaction mixture was absorbed onto silica and the title compound obtained by flash chromatography eluting with ethyl acetate/cyclohexane (1/1 ) as a white solid (179 mg). m.p. 224-226° MH⁺ = 413

Tic, Si0₂, Rf 0.60 (ethyl acetate/cyclohexane(1/1)) detection u.v./KMnO₄

Example 7

8-Bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazof1.2- alpyridine A solution of 3-bromo-pyridin-2-ylamine³ (173 mg) and 2-bromo-2-(4-fluoro- phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (371 mg) in acetonitrile (15ml) was heated at reflux overnight. On cooling to room temperature the title compound crystallised from solution and was isolated by filtration as a white solid (241 mg). m.p 266-268°

MH⁺ = 446

Analysis: Found : C,53.5;H,3.0;N,6.2;F,4.3;S,7.1

C₂oH,₄BrFN₂0₂S Requires: C,53.9;H,3.2;N,6.3;F,4.3;S,7.2% Tic, SiO_2l Rf 0.61 (Ethyl acetate/cyclohexane(2/1 )) detection u.v., KMnO₄ ³ Ref: M.Malinowski.Bull. Soc. Chim. Belg. 1988, 97, 51

Example 8

8-F luoromethyl-3-(4-f luoro-phenyl _ -2-(4-methanesulphon yl-phenyl . -im idazof 1.2- alpyridine

A solution of 3-(4-fluoro-phenyl)-2-(4-methanesulphonyl-phenyl)-imidazo[1 ,2- a]pyridine-8-methanol (200mg) in dichloromethane (10ml) was added to a cooled solution of diethylaminosulphur trifluoride (0.067 ml) in dichloromethane (4 ml) at -78° over 5 minutes. The solution was allowed to warm to room temperature over 30 minutes. Water (15 ml) was added cautiously with stirring, the organic phase was separated, dried (Na₂SO₄) and absorbed onto silica. The title compound was obtained by flash chromatography eluting with ethyl acetate/cyclohexane (1/1 ) as a white solid which was further purified by crystallisation from propan-2-ol (10 ml) yielding white crystals (85 mg). m.p. 221-222° MH* = 399 Analysis Found: C.63.1; H.3.9; N.6.8, F.9.4; S.8.1

CziHiβFsNzOzS Requires : C.63.3; H.4.05; N.7.1 , F;9.5: S,8.05%

Example 9

3- 4-Fluoro-phenvπ-2-(4-methanesulfonyl-phenvπ-7.8-dimethyl-imidazoπ .2- alpyridine A solution of 3,4-dimethyl-pyridin-2-ylamine⁴ (122 mg) and 2-bromo-2-(4-fluoro- phenyl)-1-(4-methanesulphonyl-phenyl)-ethanone (371 mg) in acetonitrile

(15ml) containing potassium carbonate (138 mg) was heated at reflux overnight.

The cooled mixture was absorbed onto silica and the title compound obtained by flash chromatography eluting with ethyl acetate/cyclohexane (1/1) as a white solid. Crystallisation from propan-2-ol (10 ml) yielded white crystals (136 mg). m.p. 228-230°

MH⁺ = 395

Analysis Found: C.66.6; H.4.7; N.6.9; F.4.8; S.8.2

C₂₂H₁₉N₂F0₂S Requires: C.67.0; H.4.85; N.7.1; F.4.8; S8.1% ⁴ Ref: W O Siegl, J Het. Chem. 1981 , 18, 1613-18

Example 10

3-(4-Fluoro-phenylV2-.4-methanesulfonyl-phenvπ-imidazof1.2-alpyridine-8- carbaldehvde

A solution of the [3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2- a]pyridin-8-yl]-methanol (500mg) and manganese (IV) oxide (1.32g) in chloroform (50ml) was heated at reflux for 16 hours. The cooled reaction mixture was filtered and the filtrate concentrated onto silica. The title compound was obtained by flash chromatography eluting with ethyl acetate/cyclohexane

(4/1 ) as a bright yellow solid (315mg). MH⁺ = 395

Analysis Found: C.63.71; H.3.55; N.6.89; S.8.07;

C₂iHι₅FN₂O₃S Requires: C.63.95; H.3.83; N.7.10; S,8.13%. Example 11

5-Bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-pheny0-8-methyl- imidazof 1.2-alPyridine

A solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methyl- imidazo[1 ,2-a]pyridine (380 mg ) in chloroform (20 ml) was treated with solid

N-bromosuccinimide (178 mg) in one portion at ambient temperature, and the resulting solution stirred overnight. Water (50 ml) was added and the organic phase collected, dried (Na₂S0₄) and absorbed onto silica. The title compound was obtained by flash chromatography eluting with cyclohexane/ethyl acetate (1/1) as a white solid (106 mg). m.p. 277-279° (dec) MH⁺ = 461 Tic, Si0₂, Rf 0.22(Ethyl acetate/cyclohexane(1/1)) detection uv, KMn04

Example 12 8-Acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazori.2- alpyridine

A suspension of 8-acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)- imidazo[1 ,2-a]pyridine (130mg) in methanol (8ml) and water (2ml) was treated with Oxone ™ (436mg) and stirred for 3h at room temperature. The resulting suspension was treated with water (50ml) and extracted with ethyl acetate

(50ml). The dried (MgS0₄) extract was evaporated and the resulting solid was treated with boiling isopropanol (3ml) for (10min), cooled and filtered to give the title compound as a white solid (85mg). m.p. 236-237° Tic Si0₂ (Et₂0) Rf 0.5 det u.v., KMnO₄

MH⁺ = 401

Example 13

6-Bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl.-8-methyl- imidazof 1.2-alpyridine A mixture of 1-amino-4-bromo-2-methylpyridine (500mg), 2-bromo-2-(4-fluoro- phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (1.0g) and acetonitrile (10ml) was refluxed under nitrogen for 20h and evaporated. The residue was triturated with diethyl ether (20ml) for 5 min, cooled and filtered. The procedure was repeated to give the title compound as a beige powder (580mg).

MH⁺ = 461

Tic Si0₂ (Et₂0) Rf 0.6 detection u.v., KMn0₄

Example 14

8-Acetyl-3-f4-fluoro-phenvπ-2-(4-methanesulfonyl-phenvπ-imidazoπ .2- alpyridine

A solution of 3-acetyl-2-aminopyridine⁵ (2.50g) and 2-bromo-2-(4-fluorophenyl)- 1-(4-methanesulphonylphenyl)ethanone (6.82g) in acetonitrile (125ml) containing sodium bicarbonate (2.31 g) was heated at reflux overnight. The mixture was filtered hot and the filtrate left to cool to room temperature. The title compound crystallised from solution and was isolated by filtration as a yellow solid (3.58g). Tic Si0₂ Rf 0.34 (ethyl acetate/hexane, 1.3:1 ) detection u.v., iodine

'H NMR 3.04(3H,s,CH₃SO₂-), 3.16(3H,s,CH₃CO-), 6.90(1 H,t,J=7.0Hz,H-6),

7.31 (2H,t,J=8.8Hz) & 7.45(2H,dd,J= 5.2Hz,8.8Hz) - C₆H₄F-, 7.85(2H,d,J=8.4Hz)

& 7.91(2H,d,J=8.4Hz) - C₆H₄S0₂, 7.93(1 H,dd,J=1.1, 7.0Hz, H-7),

8.02(1 H,dd,J=1.1 , 7.0Hz, H-5). ⁵ Ref: F.Trecourt et al, J. Chem. Soc, Perkin Trans.1 1990, 9, 2409-2415

Example 15 f3-(4-Fluoro-phenyl.-2-(4-methanesulfonyl-phenyl)-imidazof1.2-a1pyridin-8-vn- methanol

A solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2- a]pyridine-8-carboxylic acid methyl ester (1.85g) in dry tetrahydrofuran (130ml) was cooled to -78° and treated with diisobutylaluminium hydride (17.4ml;1.0M solution in dichloromethane). Once the addition was complete the mixture was allowed to warm up to 25° and stirring continued for 2 h. Methanol (80ml) was added and the mixture concentrated onto silica. The title compound was obtained by flash chromatography eluting with dichloromethane/ethanol/ammonia, 100/8/1 , as a white foam (1.54g).

MH^* = 397

Tic (SiO₂) Rf 0.28 (dichloromethane/ethanol/ammonia, 100/8/1 ) detection UN. Example 16

(±) 1 -f3-(4-fluoro-phenylV2-(4-methanesulphonyl-phenvh-imidazof 1.2-alpyridin- 8-yl1-ethan-1-ol

A solution of [3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2- a]pyridin-8-yl]-methanol (204 mg) in dry dichloromethane (10 ml) was cooled to -

78°. A solution of diisobutylaluminium hydride (1.0 M in dichloromethane 1ml) was added dropwise and the mixture allowed to warm to ambient temperature over 30 minutes. Methanol (10 ml) was added in one portion and stirring continued for a further 30 minutes. The reaction mixture was absorbed onto silica and the title compound obtained by flash chromatography eluting with ethyl acetate as a white solid (120 mg) m.p.201-203° T.l.c. SiO₂ Rf 0.45 (ethyl acetate) detection UN.

Example 17 - Tablets

a) Compound of the invention 5.0mg Lactose 95.0mg Microcrystalline Cellulose 90.0mg Cross-linked polyvinylpyrrolidone 8.0mg

Magnesium Stearate 2.0mg

Compression weight 200. Omg

The compound of the invention, microcrystalline cellulose, lactose and cross- linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and blended with the active blend. The blend is compressed into tablets using suitable punches.

b) Compound of the invention 5.0mg Lactose 165. Omg Pregelatinised Starch 20.0mg

Cross-linked polyvinylpyrrolidone 8. Omg

Magnesium Stearate 2. Omg

Compression weight 200.0mg The compound of the invention, lactose and pregelatinised starch are blended together and granulated with water. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granule. The resultant blend is compressed using suitable tablet punches.

Example 18 - Capsules

a) Compound of the invention 5.0mg

Lactose 193.0mg

Magnesium Stearate 2.0mα

Fill weight 200.0mg

The compound of the invention and pregelatinised starch are screened through a 500 micron mesh sieve, blended together and lubricated with magnesium stearate, (meshed through a 250 micron sieve). The blend is filled into hard gelatine capsules of a suitable size.

b) Compound of the invention 5.0mg

Lactose 177.0mg

Polyvinylpyrrolidone β.Omg

Cross-linked polyvinylpyrrolidone 8.0mg

Magnesium Stearate 2.0mα

Fill weight 200. Omg

The compound of the invention and lactose are blended together and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granules. The resultant blend is filled into hard gelatine capsules of a suitable size. Example 19 - Syrup

a) Compound of the invention 5. Omg

Hydroxypropyl Methylcellulose 45. Omg

Propyl Hydroxybenzoate 1.5mg Butyl Hydroxybenzoate 0.75mg

Saccharin Sodium 5.0mg

Sorbitol Solution 1.0ml

Suitable Buffers qs

Suitable flavours qs Purified Water to 10.ml

The hydroxypropyl methylcellulose is dispersed in a portion of hot purified water together with the hydroxybenzoates and the solution is allowed to cool to ambient temperature. The saccharin, sodium flavours and sorbitol solution are added to the bulk solution. The compound of the invention is dissolved in a portion of the remaining water and added to the bulk solution. Suitable buffers may be added to control the pH in the region of maximum stability. The solution is made up to volume, filtered and filled into suitable containers.

Example 20 - Injection Formulation

% w/v

Compound of the invention 1.00

Water for injections B.P. to 100.00

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the compound of the invention using dilute acid or alkali or by the addition of suitable buffer salts. Antioxidants and metal chelating salts may also be included. The solution is clarified, made up to final volume with water and the pH remeasured and adjusted if necessary, to provide 10mg/ml of the compound of formula (I).

The solution may be packaged for injection, for example by filling and sealing in ampoules, vials or syringes. The ampoules, vials or syringes may be aseptically filled (e.g. the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions) and/or terminally sterilised (e.g. by heating in an autoclave using one of the acceptable cycles). The solution may be packed under an inert atmosphere of nitrogen.

Preferably the solution is filled into ampoules, sealed by fusion of the glass and terminally sterilised.

Further sterile formulations are prepared in a similar manner containing 0.5, 2.0 and 5% w/v of the compound of formula (I), so as to provide respectively 5, 20 and 50mg/ml of the compound of formula (I).

Biological Data

Inhibitory activity against human COX-1 and COX-2 was assessed in COS cells which have been stably transfected with cDNA for human COX-1 and human

COX-2. 24 Hours prior to experiment, COS cells were transferred from the 175cm² flasks in which they were grown, onto 24-well cell culture plates using the following procedure. The incubation medium, being Dulbecco's modified eagles medium (DMEM) to which had been added heat inactivated foetal calf serum (10%v/v), penicillin (100U /ml), streptomycin (100μg/ml) and geneticin

(600μg/ml), was removed from a flask of confluent cells (1 flask at confluency contains approximately 1x10⁷ cells). 10ml of phosphate buffered saline (PBS) was added to the flask to wash the cells. Having removed the PBS, cells were rinsed in 10ml trypsin for 20 seconds, after which the trypsin was removed and the flask placed in an incubator (37°) for 1-2 minutes until cells became loose.

The flask was then removed from the incubator and cells resuspended in 10ml of fresh incubation medium. The contents of the flask was transferred to a 250ml sterile container and the volume of incubation medium subsequently made up to 100ml. 1ml cell suspension was pipetted into each well of 4x24-well cell culture plates. The plates were then placed in an incubator (37°C, 95% air/5% CO₂) overnight. If more than 1 flask was used, the cells were combined before being dispensed into the 24-well plates.

Following the overnight incubation, the incubation medium was completely removed from the 24-well cell culture plates and replaced with 250μl fresh

DMEM (37°C). Test compounds were made up to 250x the required test concentration in DMSO and were added to the wells in a volume of 1μl. Plates were then mixed gently by swirling and then placed in an incubator for 1 hour (37°C, 95% air/5% CO2). Following the incubation period, 10μl of arachidonic acid (750μM) was added to each well to give a final arachidonic acid concentration of 30μM. Plates were then incubated for 15 minutes, after which the incubation medium was removed from each well of the plates and stored at -20°C, prior to determination of prostaglandin E₂ (PGE2) levels using enzyme immunoassay. The inhibitory potency of the test compounds was expressed as an IC₅₀ value, which is defined as the concentration of the compound required to inhibit the PGE2 release from the cells by 50%. The selectivity ratio of inhibition of COX-1 versus COX-2 was calculated by comparing respective IC₅₀ values.

The following IC₅₀ values for inhibition of COX-2 and COX-1 were obtained for compounds of the invention:

Claims

1. Compounds of formula (I)

and pharmaceutically acceptable derivatives thereof in which:

R represents halogen;

R¹ and R² are independently selected from H, halogen, C.^alkyl, C.^alkyl substituted by one or more fluorine atoms, SC_.^alkyl, C(0)H or C(0)C_._,alkyl; and R³ represents

2. Compounds as claimed in claim 1 wherein R³ represents methyl.

3. Compounds as claimed in claim 1 or 2 wherein R° represents fluorine.

4. Compounds as claimed in any one of claims 1 to 3 wherein R¹ represents H, chlorine, bromine, (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH₂F or CF₃), C^hydroxyalkyl (e.g. CH₂OH or

CH(OH)CH₃), SC.-4a.kyl (e.g. SCH₃), C(0)H or C(0)C._,alkyl (e.g. C(0)CH₃).

5. Compounds as claimed in any one of claims 1 to 4 wherein R² represents H, chlorine, bromine or Cι- alkyl (e.g. methyl).

6. Compounds as claimed in any one of claims 1 to 5 wherein R° represents fluorine; R¹ represents H, chlorine, bromine, Cι-_.alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH₂F or CF₃), (e.g. CH₂OH or CH(OH)CH₃), SC^alkyl (e.g. SCH₃), C(O)H or C(0)d_,alkyl (e.g. C(O)CH₃); R² represents H, chlorine, bromine, or d^alkyl (e.g. methyl); and R³ represents methyl.

7. Compounds as claimed in any one of claims 1 to 6 wherein R° represents fluorine; R¹ represents H, chlorine, bromine, methyl, CH₂F, CF₃, SCH₃, C(0)H or C(0)CH₃; R² represents H, bromine or methyl; and R³ represents methyl.

8. Compounds as claimed in any one of claims 1 to 7 wherein R¹ is at the 8-position; and R² is at the 7-position or, when R¹ is other than H, the 5-, 6- or

7-position.

9. Compounds as claimed in any one of claims 1 to 8 wherein R¹ is at the 8-position; and R² is at the 7-position or, when R¹ is d^alkyl (e.g. methyl), the 5-or 7-position.

10. Compounds as claimed in any one of claims 1 to 9 wherein R¹ represents

C(0)CH₃.

11. 8-Acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2- ajpyridine and pharmaceutically acceptable derivatives thereof.

12. Compounds as clamed in any of claims 1 to 11 wherein the compound of formula (I) is in the form of a hydrochloride, hydrobromide or sulphate.

13. A process for the preparation of compound of formula (I) and pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 12, which comprises:

(A) reacting a compound of formula (II)

(II) or a protected derivative thereof, wherein Lg represents a leaving group, with a compound of formula (III)

or a protected derivative thereof; or

(B) reacting a compound of formula (IV)

or a protected derivative thereof with an oxidising agent; or

(C) interconversion of a compound of formula (I) into another compound of formula (I); or

(D) deprotecting a protected derivative of compound of formula (I);

and optionally converting compounds of formula (I) prepared by any one of processes (A) to (D) into pharmaceutically acceptable derivatives thereof.

14. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12 in admixture with one or more physiologically acceptable carriers or excipients.

15. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12 for use in human or veterinary medicine.

16. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12 for use in the treatment of a condition which is mediated by selective inhibition of COX-2

17. A method of treating a human or animal subject suffering from a condition which is mediated by selective inhibition of COX-2 which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative as defined in any one of Claims 1 to 12.

18. The use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12 for the manufacture of a therapeutic agent for the treatment of inflammatory disorders.

19. A method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12.